Morphine is the prototype of the class of opioid analgesic drugs which exert their effects by activating opioid receptors within the brain. When morphine is referred to individually in this application, this reference is meant to encompass other opioid drugs and is not meant to be morphine exclusively. Historically, narcotics have been used since the 18th century in the forms of oral or injectable morphine or opium in order to accomplish pain relief. Morphine is considered to be unsurpassed as an analgesic for severe pain.
Unfortunately, morphine and other opioid drugs have a number of severe side effects which hamper their wide spread use and acceptance by both physicians and patients. These side effects include: addiction, nausea, inhibition of breathing, somnolence and dysphoria, all of which are mediated by morphine's action within the brain. It is Still the current belief that narcotics ingested or injected will cross to the blood stream and from there go to the brain where there are morphine receptors. At that time, the narcotics are believed to attach to these morphine receptors and create a dullness of the pain but with all of the side effects described above. Of course, the worst potential effect is the addiction that can occur if the morphine is used beyond a few days or weeks on a continuous basis.
Because of the fear of addiction, the use of morphine as an analgesic has been restricted. In addition, major research efforts have been directed toward the development of morphine-like drugs that act within the brain but are devoid of the side effects. The market for these other drugs has never fully materialized because these drugs were not perceived as having the same analgesic properties of morphine and because typically these drugs were not produced to be both available in oral and injectable formats.
In the past ten years the intraspinal method of treating pain has been developed tremendously but, as more extensive use was made of this technique, a number of serious problems developed. The first problem is that the intraspinal method of treatment requires a spinal tap which of course necessitates the use of a needle to the spinal cord. The second problem results from the first in that if it is necessary to use the intraspinal method over a period of time, such as two or three weeks, medication must be injected into the spine for this period of time and the continuous needle sticks into the spine has potential hazards. Further, if it is necessary to use the intraspinal method over time, even though the dosage is substantially less compared to oral or intravenous dosages, there is still a high potential for addiction and with such addiction the resultant problems of withdrawal and its associated side effects.
Although intraspinal application of narcotics is still used to alleviate pain after surgery, this technique has the limitations with the potential for addiction as described above. In addition, it has been determined that with frail patients there is the risk that the patient can stop breathing and there have been a number of cases of respiratory arrest after the administration of narcotics using the intraspinal technique. Further, the intraspinal technique of administering narcotics creates difficulty with male patients and especially with elderly male patients in that there can be problems with urination and with consequent problems of urine retention. Finally, this intraspinal technique produces a problem of itching and the sequences of continuous itching can be debilitating.
In more recent studies it was discovered that opioid receptors may also be located in other peripheral tissues. This was reported in Stein C., Millan M. J., Shippenberg T. S., Herz A.: Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci Lett 1988, 84:225-228 and in Stein C., Millan M. J., Yassouridis A., Herz A.: Antinociceptive effects of mu-and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action. Eur J Pharmacol 1988, 155:255-264. Subsequently, a large number of animal experiments were performed in Dr. Stein's laboratory, characterizing peripheral opioid receptors and their activation by morphine and other opioid drugs. This is reviewed in Stein C.: Peripheral mechanisms of opioid analgesia. Anesth Analg 1993, 76:182-191 and in Stein C., Lehrgerger K., Yassouridis A., Khoury G.: Opioids as novel intraarticular agents in arthritis. In: Progress in Pain Research and Management, ed. by Fields H. L., Liebeskind J. C. IASP Press, Seattle 1994, 1:289-296. A most important determination from these various studies is that the doses of the drugs required to produce analgesia in the peripheral tissues are extremely small and therefore devoid of the above mentioned side effects produced by dosages sufficient to operate on the brain.
In addition, it was determined that the endogenous ligands of peripheral opioid receptors (endorphines, the body's own pain killers) are located within the inflamed tissue. It was also determined that the endorphines can produce intrinsic analgesia within peripheral tissues both in animals and in humans (Stein Anesth. Analg. (1993) 182-191). A further determination was that the peripheral opioid effects are more pronounced in inflamed than in non-inflamed tissues.